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Background: With an increasing understanding of the antitumor immune response, considerable progress has been made in the field of tumor immunotherapy in the last decade. Inhibition of histone deacetylases represents a new strategy in tumor therapy and histone deacetylase inhibitors have been recently developed and validated as potential antitumor drugs. In addition to the direct antitumor effects, histone deacetylase inhibitors have been found to have the ability to improve tumor recognition by immune cells that may contribute to their antitumor activity. These immunomodolutory effects are desirable, and their in-depth comprehension will facilitate the design of novel regimens with improved clinical efficacy., Objective: Our goal here is to review recent developments in the application of histone deacetylase inhibitors as immune modulators in cancer treatment., Methods: Systemic compilation of the relevant literature in this field., Results & Conclusion: In this review, we summarize recent advances in the understanding of how histone deacetylase inhibitors alter immune process and discuss their effects on various cytokines. We also discuss the challenges to optimize the use of these inhibitors as immune modulators in cancer treatment. Information gained from this review will be valuable to this field and may be helpful for designing tumor immunotherapy trials involving histone deacetylase inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Although bortezomib (BTZ) remains a first-line agent for multiple myeloma (MM) therapy, the development of BTZ resistance has become an indicator of poor prognosis in MM patients. It is thus urgent to develop strategies to restore the vulnerability of MM to BTZ. This study demonstrated, for the first time, that UbcH10 is highly expressed in BTZ-resistant myeloma cell lines U-266/BTZ, NCI-H929/BTZ and RPMI-8226/BTZ, which is attributed to the inactivation of post-transcriptional control. The in-depth study revealed that during the development of BTZ resistance in these cells, the hsa-miR-631 levels were decreased, which resulted in the increased expression of the target gene UbcH10. We also found that the multiple drug-resistant protein MDR1 exhibited a positive correlation with UbcH10 due to the reduced ubiquitination of MDR1, which was caused by high UbcH10 expression. Following overexpression of miR-631, both BTZ sensitivity and BTZ-induced apoptosis were enhanced in the resistant cells. Meanwhile, resensitization by miR-631 overexpression was blocked by exogenous expression of UbcH10, which was not regulated by intracellular miR-631. In conclusion, the miR-631/UbcH10/MDR1 pathway is closely associated with the development of BTZ resistance in myeloma cells, and the overexpression of miR-631 can significantly improve BTZ sensitivity in resistant myeloma cells.

Lack of satisfactory specificity towards tumor cells and poor intracellular delivery efficacy are the major drawbacks with conventional cancer chemotherapy. Conjugated anticancer drugs to targeting moieties e.g. to peptides with the ability to recognize cancer cells and to cell penetrating peptide can improve these characteristics, respectively. Combining a tumor homing peptide with an appropriate cell-penetrating peptide can enhance the tumor-selective internalization efficacy of the carrying cargo molecules. In the present study, the breast cancer homing ability of SP90 peptide and the synergistic effect of SP90 with a cell-penetrating peptide(C peptide) were evaluated. SP90 and chimeric peptide SP90-C specifically targeted cargo molecule into breast cancer cells, especially triple negative MDA-MB-231 cell, in a dose- and time-dependent manner, but not normal breast cells and other cancer cells, while C peptide alone had no cell-selectivity. SP90-C increased the intracellular delivery efficiency by 12-fold or 10-fold compared to SP90 or C peptide alone, respectively. SP90 and SP90-C conjugation increased the anti-proliferative and apoptosis-inducing activity of HIV-1 Vpr, a potential novel anticancer protein drug, to breast cancer cell but not normal breast cell by arresting cells in G2/M phase. With excellent breast cancer cell-selective penetrating efficacy, SP90-C appears as a promising candidate vector for targeted anti-cancer drug delivery. SP90-VPR-C is a potential novel breast cancer-targeted anticancer agent for its high anti-tumor activity and low toxicity., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A series of shikonin analogs have been synthesized in a one-pot reaction of quinizarin with β,γ-unsaturated aldehydes in MeOH under mild conditions and investigated for their cytotoxicity against four cancer cell lines and one normal cell line. The synthesized compounds were found to be cytotoxic against HeLa cells with no apparent toxicity against normal cell line. Further modification led to the discovery of a novel tetracyclic anthraquinone (4b/4b') with potent cytotoxic activities against cervical, breast and pancreatic cancer cell lines with no significant effect on the growth of the control mammary epithelial cell line MCF-10. The good cytotoxicity and selectivity of compound 4b/4b' suggest that it could be a promising lead for further optimization., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of hydroxyanthraquinones having an alkylating N-mustard pharmacophore at 1'-position were synthesized via a bioisostere approach to evaluate their cytotoxicity against four tumor cell lines (MDA-MB-231, HeLa, MCF-7 and A549). These compounds displayed significant in vitro cytotoxicity against MDA-MB-231 and MCF-7 cells, reflecting the excellent selectivity for the human breast cancer. Among them, compound 5k was the most cytotoxic with IC50 value of 0.263 nM and is more potent than DXR (IC50 = 0.294 nM) in inhibiting the growth of MCF-7 cells. The excellent cytotoxicity and good selectivity of compound 5k suggest that it could be a promising lead for further design and development of anticancer agents, especially for breast cancer., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A series of conjugates of 5-Fluorouracil (5-FU) and emodin were synthesized by coupling trimethyl emodin with N(1), N(3) dialkylated 5-FU. The 5-FU moiety contained various substituents at the N(3)-position were linked to the 2-position of trimethyl emodin via a methylene linkage. Their cytotoxicity against three cancer cell lines and one noncancerous cell were studied. The results revealed that some of conjugates exhibited better or comparable in vitro antitumor activity to 5-FU and emodin and low toxicity in the normal cell. The structure-activity relationship study showed N(3)-aromatic substituent was important for their cytotoxic activity., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

In an attempt to develop potent and selective antitumor agents, a series of 6- and 2-(1-substituted-thio-4-methylpent-3-enyl)-5,8-dimethoxynaphthalene-1,4-diones were designed and synthesized. The cytotoxicities of these compounds were evaluated in vitro against BEL-7402, HT-29 and SPC-A1 cell lines. The pharmacological results showed that most of the prepared compounds displayed the excellent selective cytotoxicity toward HT-29 cells. From the structure-activity relationships we may conclude that the introduction of a thioether functional group at the 1'-position in the side chain of shikonin is associated with an increase in cytotoxicity.

1,4-Dihydroxyanthraquinones are widely featured in numerous natural products and drugs. It is important to be able to functionalize the 1,4-dihydroxyanthraquinone skeleton through a simple yet efficient transformation, which could be potentially useful for the drug discovery process. We describe herein a simple and efficient method to derivatize 1,4-dihydroxyanthraquinone by using a modified Marschalk reaction. This method provides a clear advantage over traditional approaches, which often require the protection and deprotection of the OH groups. We also demonstrate the applicability of this reaction to other hydroxyanthraquinones and aminoanthraquinones. [ABSTRACT FROM AUTHOR]